Distribution of hepatitis B virus infection in Namibia

Background. Namibia regards hepatitis B virus (HBV) infection as a public health problem and introduced hepatitis B vaccinations for infants during 2009. However, information on HBV infection in the country remains limited, and effective public health interventions may be compromised in the absence of adequate evidence-based data. Available data from the World Health Organization (WHO) estimate that 15 - 60% of the normal population in many African countries may be positive for one or more of the HBV serological markers. Objective. To investigate the distribution of HBV infection in Namibia, using available laboratory data for 2013. Methods. A cross-sectional descriptive study was conducted using pre-existing electronic laboratory data on HBV infection. The data were retrieved from the central Namibia Institute of Pathology laboratory in Windhoek during January - December 2013. Tests were done on the following three main groups: (i) pregnant women during routine antenatal care (ANC) visits; (ii) patients with HIV/AIDS during antiretroviral therapy clinic visits; and (iii) any other individual suspected of having HBV infection. Results. Of a total of 77 238 hepatitis B surface antigen test results retrieved countrywide, 9 087 (11.8%) were positive. Of the positive results, 246/9 087 (2.7%) were in children aged 0 - 14 years, with the sexes equally affected. HBV infections increased markedly, particularly among females, in the age group 15 - 39 years, reaching a peak in the age group 30 - 34 years. Routine screening of pregnant women for HBV during ANC visits was found to be systematically conducted in only two regions, Ohangwena and Khomas. Conclusions. This study showed high proportions of positive results in pregnant women, patients with HIV/AIDS and individuals suspected of having HBV infection. The Ministry of Health and Social Services and stakeholders may wish to consider improving the routine and surveillance reporting systems for viral hepatitis and uptake of screening for pregnant women in all regions, and expanding HBV screening to other population groups. Population-based or similar studies are therefore required to determine the HBV prevalence and risk factors. This will assist Namibia in developing appropriate national viral hepatitis strategies as per WHO recommendations.S Afr Med J 2017;107(10):882-88

Fixed-time artificial insemination in beef cattle

which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Background: The study was designed to test the effect of fixed-time artificial insemination (fixed-AI) after the slightly modified Ovsynch protocol on the pregnancy rate in beef cattle in Finnish field conditions. The modification was aimed to optimize the number of offsprings per AI dose. Methods: Ninety Charolais cows and heifers were entered into the program an average of 1.8 times. Thus, 164 animal cases were included. Animals were administered 10-12 μg of buserelin. Seven days later animals without a corpus luteum (CL) were rejected (20.7%) while the remaining 130 cases with a CL were administered prostaglandin F2α, followed 48 h later with a second injection of buserelin (8-10 μg). Fixed-AI was performed 16-20 hours after the last injection. Results: The pregnancy rate was 51.5 % (67/130). The pregnancy rate after a short interval (50-70 d) from calving to entering the program was significantly higher than that after a long interval (>70 d). Conclusion: This protocol seems to give acceptable pregnancy results in beef herds and its effect on saving labour is notable

Subsequent Chemotherapy and Treatment Patterns After Abiraterone Acetate in Patients with Metastatic Castration-resistant Prostate Cancer: Post Hoc Analysis of COU-AA-302.

Background Treatment patterns for metastatic castration-resistant prostate cancer (mCRPC) have changed substantially in the last few years. In trial COU-AA-302 (chemotherapy-naïve men with mCRPC), abiraterone acetate plus prednisone (AA) significantly improved radiographic progression-free survival and overall survival (OS) when compared to placebo plus prednisone (P).Objective This post hoc analysis investigated clinical responses to docetaxel as first subsequent therapy (FST) among patients who progressed following protocol-specified treatment with AA, and characterized subsequent treatment patterns among older (≥75 yr) and younger (<75 yr) patient subgroups.Design, setting, and participants Data were collected at the final OS analysis (96% of expected death events). Subsequent therapy data were prospectively collected, while response and discontinuation data were collected retrospectively following discontinuation of the study drug.Intervention At the discretion of the investigator, 67% (365/546) of patients from the AA arm received subsequent treatment with one or more agents approved for mCRPC.Outcome measurements and statistical analysis Efficacy analysis was performed for patients for whom baseline and at least one post-baseline prostate-specific antigen (PSA) values were available.Results and limitations Baseline and at least one post-baseline PSA values were available for 100 AA patients who received docetaxel as FST. While acknowledging the limitations of post hoc analyses, 40% (40/100) of these patients had an unconfirmed ≥50% PSA decline with first subsequent docetaxel therapy, and 27% (27/100) had a confirmed ≥50% PSA decline. The median docetaxel treatment duration among these 100 patients was 4.2 mo. Docetaxel was the most common FST among older and younger patients from each treatment arm. However, 43% (79/185) of older patients who progressed on AA received no subsequent therapy for mCRPC, compared with 17% (60/361) of younger patients.Conclusions Patients with mCRPC who progress with AA treatment may still derive benefit from subsequent docetaxel therapy. These data support further assessment of treatment patterns following AA treatment for mCRPC, particularly among older patients.Trial registration ClinicalTrials.gov NCT00887198.Patient summary Treatment patterns for advanced prostate cancer have changed substantially in the last few years. This additional analysis provides evidence of clinical benefit for subsequent chemotherapy in men with advanced prostate cancer whose disease progressed after treatment with abiraterone acetate. Older patients were less likely to be treated with subsequent therapy

Use of Tissue-Specific MicroRNA to Control Pathology of Wild-Type Adenovirus without Attenuation of Its Ability to Kill Cancer Cells

Replicating viruses have broad applications in biomedicine, notably in cancer virotherapy and in the design of attenuated vaccines; however, uncontrolled virus replication in vulnerable tissues can give pathology and often restricts the use of potent strains. Increased knowledge of tissue-selective microRNA expression now affords the possibility of engineering replicating viruses that are attenuated at the RNA level in sites of potential pathology, but retain wild-type replication activity at sites not expressing the relevant microRNA. To assess the usefulness of this approach for the DNA virus adenovirus, we have engineered a hepatocyte-safe wild-type adenovirus 5 (Ad5), which normally mediates significant toxicity and is potentially lethal in mice. To do this, we have included binding sites for hepatocyte-selective microRNA mir-122 within the 39 UTR of the E1A transcription cassette. Imaging versions of these viruses, produced by fusing E1A with luciferase, showed that inclusion of mir-122 binding sites caused up to 80-fold decreased hepatic expression of E1A following intravenous delivery to mice. Animals administered a ten-times lethal dose of wild-type Ad5 (5610 10 viral particles/mouse) showed substantial hepatic genome replication and extensive liver pathology, while inclusion of 4 microRNA binding sites decreased replication 50-fold and virtually abrogated liver toxicity. This modified wild-type virus retained full activity within cancer cells and provided a potent, liver-safe oncolytic virus. In addition to providing many potent new viruses for cancer virotherapy, microRNA control of virus replication should provide a new strategy for designing safe attenuated vaccines applied across a broad range of viral disease

Annual review article: Is it time to rethink the gender agenda in entrepreneurship research?

This article develops a critique of contemporary approaches to analysing the impact of gender upon entrepreneurial propensity and activity. Since the 1990s, increasing attention has been afforded to the influence of gender upon women’s entrepreneurial behaviour; such analyses have highlighted an embedded masculinity within the entrepreneurial discourse which privileges men as normative entrepreneurial actors. Whilst invaluable in revealing a prevailing masculine bias within entrepreneurship, this critique is bounded by positioning women as a proxy for the gendered subject. This is a potentially limiting analysis that does not fully recognise gender as a human property with myriad articulations enacted throughout entrepreneurial activity. To progress debate, we engage more deeply with the notion of gender as a multiplicity exploring the implications of such for future studies of entrepreneurial activity

Variants of ADRA2A are associated with fasting glucose, blood pressure, body mass index and type 2 diabetes risk: meta-analysis of four prospective studies

AIMS/HYPOTHESIS: We quantified the effect of ADRA2A (encoding α-2 adrenergic receptor) variants on metabolic traits and type 2 diabetes risk, as reported in four studies. METHODS: Genotype data for ADRA2A single nucleotide polymorphisms (SNPs) rs553668 and rs10885122 were analysed in >17,000 individuals (1,307 type 2 diabetes cases) with regard to metabolic traits and type 2 diabetes risk. Two studies (n = 9,437), genotyped using the Human Cardiovascular Disease BeadChip, provided 12 additional ADRA2A SNPs. RESULTS: Rs553668 was associated with per allele effects on fasting glucose (0.03 mmol/l, p = 0.016) and type 2 diabetes risk (OR 1.17, 95% CI 1.04-1.31; p = 0.01). No significant association was observed with rs10885122. Of the 12 SNPs, several showed associations with metabolic traits. Overall, after variable selection, rs553668 was associated with type 2 diabetes risk (OR 1.38, 95% CI 1.09-1.73; p = 0.007). rs553668 (per allele difference 0.036 mmol/l, 95% CI 0.008-0.065) and rs17186196 (per allele difference 0.066 mmol/l, 95% CI 0.017-0.115) were independently associated with fasting glucose, and rs17186196 with fasting insulin and HOMA of insulin resistance (4.3%, 95% CI 0.6-8.1 and 4.9%, 95% CI 1.0-9.0, respectively, per allele). Per-allele effects of rs491589 on systolic and diastolic blood pressure were 1.19 mmHg (95% CI 0.43-1.95) and 0.61 mmHg (95% CI 0.11-1.10), respectively, and those of rs36022820 on BMI 0.58 kg/m(2) (95% CI 0.15-1.02). CONCLUSIONS/INTERPRETATION: Multiple ADRA2A SNPs are associated with metabolic traits, blood pressure and type 2 diabetes risk. The α-2 adrenergic receptor should be revisited as a therapeutic target for reduction of the adverse consequences of metabolic trait disorders and type 2 diabetes

The Complete Chloroplast and Mitochondrial Genome Sequences of Boea hygrometrica: Insights into the Evolution of Plant Organellar Genomes

The complete nucleotide sequences of the chloroplast (cp) and mitochondrial (mt) genomes of resurrection plant Boea hygrometrica (Bh, Gesneriaceae) have been determined with the lengths of 153,493 bp and 510,519 bp, respectively. The smaller chloroplast genome contains more genes (147) with a 72% coding sequence, and the larger mitochondrial genome have less genes (65) with a coding faction of 12%. Similar to other seed plants, the Bh cp genome has a typical quadripartite organization with a conserved gene in each region. The Bh mt genome has three recombinant sequence repeats of 222 bp, 843 bp, and 1474 bp in length, which divide the genome into a single master circle (MC) and four isomeric molecules. Compared to other angiosperms, one remarkable feature of the Bh mt genome is the frequent transfer of genetic material from the cp genome during recent Bh evolution. We also analyzed organellar genome evolution in general regarding genome features as well as compositional dynamics of sequence and gene structure/organization, providing clues for the understanding of the evolution of organellar genomes in plants. The cp-derived sequences including tRNAs found in angiosperm mt genomes support the conclusion that frequent gene transfer events may have begun early in the land plant lineage

Prior Endocrine Therapy Impact on Abiraterone Acetate Clinical Efficacy in Metastatic Castration-resistant Prostate Cancer: Post-hoc Analysis of Randomised Phase 3 Studies.

The duration of prior hormonal treatment can predict responses to subsequent therapy in patients with metastatic castration-resistant prostate cancer (mCRPC).To determine if prior endocrine therapy duration is an indicator of abiraterone acetate (AA) sensitivity.Post-hoc exploratory analysis of randomised phase 3 studies examining post-docetaxel (COU-AA-301) or chemotherapy-naïve mCRPC (COU-AA-302) patients receiving AA. The treatment effect on overall survival (OS), radiographic progression-free survival (rPFS), and prostate-specific antigen (PSA) response analysed by quartile duration of prior gonadotropin-releasing hormone agonists (GnRHa) or androgen receptor (AR) antagonist.Patients were randomised to AA (1000mg, orally once daily) plus prednisone (5mg, orally twice daily) or placebo plus prednisone. Prior endocrine therapy was GnRHa (COU-AA-301, n=1127 [94%]; COU-AA-302, n=1057 [97%], 45.1 mo or 36.7 mo median duration, respectively) and/or orchiectomy (COU-AA-301, n=78 [7%] COU-AA-302, n=44 [4%]); castrated patients received prior AR antagonists (COU-AA-301, n=1015 [85%]; COU-AA-302, n=1078 [99%], 15.7 mo or 16.1 mo median duration, respectively).Cox model was used to obtain hazard ratio and associated 95% confidence interval with statistical inference by log rank statistic.Clinical benefit with AA was observed for OS, rPFS, and PSA response for nearly all quartiles with GnRHa or AR antagonists in both COU-AA-301 and COU-AA-302. In COU-AA-301, patients with a longer duration of prior endocrine therapy tended to have greater AA OS, rPFS, and PSA response benefit, with lead-time chemotherapy bias potentially impacting COU-AA-301 results. Time to castration resistance was not captured. This analysis is limited as a post-hoc exploratory analysis.In the COU-AA-301 and COU-AA-302 studies, AA produced clinical benefits regardless of prior endocrine therapy duration in patients with mCRPC.Metastatic castration-resistant prostate cancer patients derived clinical benefits with abiraterone acetate regardless of prior endocrine therapy duration

Interleukin-6 trans signalling enhances photodynamic therapy by modulating cell cycling

Photodynamic therapy (PDT) of solid tumours causes tissue damage that elicits local and systemic inflammation with major involvement of interleukin-6 (IL-6). We have previously reported that PDT-treated cells lose responsiveness to IL-6 cytokines. Therefore, it is unclear whether PDT surviving tumour cells are subject to regulation by IL-6 and whether this regulation could contribute to tumour control by PDT. We demonstrate in epithelial tumour cells that while the action of IL-6 cytokines through their membrane receptors is attenuated, regulation by IL-6 via trans-signalling is established. Soluble interleukin-6 receptor-α (IL-6Rα) (sIL-6Rα) and IL-6 were released by leucocytes in the presence of conditioned medium from PDT-treated tumour cells. Cells that had lost their membrane receptor IL-6Rα due to PDT responded to treatment with the IL-6R–IL-6 complex (Hyper-IL-6) with activation of signal transducers and activator of transcription (STAT3) and ERK. Photodynamic therapy-treated cells, which were maintained during post-PDT recovery in presence of IL-6 or Hyper-IL-6, showed an enhanced suppression of proliferation. Cytokine-dependent inhibition of proliferation correlated with a decrease in cyclin E, CDK2 and Cdc25A, and enhancement of p27kip1 and hypophosphorylated Rb. The IL-6 trans-signalling-mediated attenuation of cell proliferation was also effective in vivo detectable by an improved Colon26 tumour cure by PDT combined with Hyper-IL-6 treatment. Prevention of IL-6 trans-signalling using soluble gp130 reduced curability. The data suggest that the post-PDT tumour milieu contains the necessary components to establish effective IL-6 trans-signalling, thus providing a means for more effective tumour control

HPRT Deficiency Coordinately Dysregulates Canonical Wnt and Presenilin-1 Signaling: A Neuro-Developmental Regulatory Role for a Housekeeping Gene?

We have used microarray-based methods of global gene expression together with quantitative PCR and Western blot analysis to identify dysregulation of genes and aberrant cellular processes in human fibroblasts and in SH-SY5Y neuroblastoma cells made HPRT-deficient by transduction with a retrovirus stably expressing an shRNA targeted against HPRT. Analysis of the microarray expression data by Gene ontology (GO) and Gene Set Enrichment Analysis (GSEA) as well as significant pathway analysis by GeneSpring GX10 and Panther Classification System reveal that HPRT deficiency is accompanied by aberrations in a variety of pathways known to regulate neurogenesis or to be implicated in neurodegenerative disease, including the canonical Wnt/β-catenin and the Alzheimer's disease/presenilin signaling pathways. Dysregulation of the Wnt/β-catenin pathway is confirmed by Western blot demonstration of cytosolic sequestration of β-catenin during in vitro differentiation of the SH-SY5Y cells toward the neuronal phenotype. We also demonstrate that two key transcription factor genes known to be regulated by Wnt signaling and to be vital for the generation and function of dopaminergic neurons; i.e., Lmx1a and Engrailed 1, are down-regulated in the HPRT knockdown SH-SY5Y cells. In addition to the Wnt signaling aberration, we found that expression of presenilin-1 shows severely aberrant expression in HPRT-deficient SH-SY5Y cells, reflected by marked deficiency of the 23 kDa C-terminal fragment of presenilin-1 in knockdown cells. Western blot analysis of primary fibroblast cultures from two LND patients also shows dysregulated presenilin-1 expression, including aberrant proteolytic processing of presenilin-1. These demonstrations of dysregulated Wnt signaling and presenilin-1 expression together with impaired expression of dopaminergic transcription factors reveal broad pleitropic neuro-regulatory defects played by HPRT expression and suggest new directions for investigating mechanisms of aberrant neurogenesis and neuropathology in LND and potential new targets for restoration of effective signaling in this neuro-developmental defect